Glenmark Pharmaceuticals Limited - 708270 - 07/11/2025

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Warning Letter 320-25-92

July 11, 2025

AMENDED
(This letter replaces Warning Letter No. 320-25-92 dated July 11, 2025.)

Dear Mr. Gupta:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Glenmark Pharmaceuticals Limited, FEI 3008565058, located at Phase – II, Sector III, Plot No 2, Pharma Zone, SEZ, Pithampur, Madhya Pradesh, 454774 India, from February 3 to 14, 2025.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your March 10, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

A. There were several dissolution failures for potassium chloride extended-release (ER) capsules during stability testing.

One of the potential root causes you described was the occasional “(b)(4)” of your incoming active pharmaceutical ingredient (API). You define “(b)(4)” as the “presence of (b)(4) API (b)(4) and (b)(4) API (b)(4)” that “leads to (b)(4) in the particle size distribution.” “(b)(4)” appears to be insufficient to explain the dissolution failures.

You have a process control in place to (b)(4) the API for desired particle size prior to (b)(4). You also had both passing and failing drug product batches that used API lots with a “(b)(4)”, and the same API lot number, (b)(4), was noted to be used in both an out-of-specification (OOS) drug product batch and a passing drug product batch.

You identified a possible second root cause in a subsequent investigation addendum report, dated January 20, 2025, as a process change from 2021 to adjust the (b)(4) content of your (b)(4) solution from (b)(4) % to (b)(4) %. However, your investigation report did not include sufficient scientific evidence to support this root cause or demonstrate you considered all potassium chloride ER capsule process changes that may impact the dissolution results.

We acknowledge that, in June 2024, you recalled all batches of potassium chloride ER capsules within expiry from the U.S. market. However, your investigation was not sufficient to adequately determine root cause(s) of your repeated dissolution failures during long-term stability testing.

In your response, you state you reviewed the process changes for the potassium chloride ER capsules since product launch. The response does not sufficiently address all changes that could have contributed to the dissolution failures. Notably, you identify the increase in the (b)(4) content of the (b)(4) solution as a change that was relevant to the dissolution failures. You state that the dissolution failures occurred in batches manufactured after the implementation of this change.

However, you do not address other significant changes that could have impacted dissolution. For example, in 2017, you implemented a process change involving the use of a (b)(4) for (b)(4) to replace your (b)(4), along with changing (b)(4) process parameters, such as increasing (b)(4) of the (b)(4) and increasing the (b)(4) of the (b)(4). These process changes may potentially affect drug performance, including the dissolution profile. There is no indication you investigated them adequately as part of your root cause analysis for these dissolution failures.

Also, your response explains that (b)(4) particle sizes and non-uniform (b)(4) can lead to poor (b)(4) formation during the (b)(4) process. You indicate this issue can cause (b)(4) formation over time. You performed a research study to assess the impact of different concentrations of the (b)(4) content in the (b)(4) solution onto the particles and storing the product under accelerated conditions. You documented faster dissolution rates when using a higher concentration ((b)(4)%) of (b)(4) solution. While you hypothesized the (b)(4) are associated with dissolution failures, your study did not provide adequate data on (b)(4) morphology, including scanning electron microscope (SEM) analysis used in other aspects of your investigation, to support your conclusion.

Your response states the root cause for the dissolution failures is the combined impact of the API particle size distribution and (b)(4) solution (b)(4) content. To evaluate the combination of these variables, you are conducting a design of experiment (DoE) study that evaluates two different particle sizes of your API and (b)(4) different (b)(4) contents of the (b)(4) solution. These engineering batches will then be placed on stability and tested for dissolution. You explain the purpose of this DoE is to verify the assignable cause(s) for your product’s dissolution failures.

However, your DoE does not include other process parameters previously determined to be critical to controlling dissolution. Specifically, you had concluded that in-process “generation of (b)(4) is controlled by keeping (b)(4) between (b)(4) at a steady rate during (b)(4),” and “excessive (b)(4) generated during processing leads to uneven (b)(4) in the batch” based on previous engineering studies.

B. Your investigations into dissolution failures during stability testing of another drug product, (b)(4) capsule, did not adequately support your root cause. Specifically, your root cause concluded variations in your process parameters, such as the (b)(4) were contributing to the failing dissolution results for this product. You proposed changes to the master batch record parameters for the (b)(4) process as your corrective action and preventative action (CAPA), but did not perform sufficient validation studies to confirm your root cause determination prior to distribution of more batches.

Instead, you planned on verifying your CAPA after revising the master batch record. Given the multiple product failures and significant lapse in state of control, process validation studies should have been completed prior to implementation of revised master batch records. You manufactured and distributed several additional batches of (b)(4) capsules prior to suspending manufacturing of this drug product.

In your response, you state you manufactured batches of (b)(4) capsules with “stringent process parameters within the validated range” and believed that process validation studies were not needed for “fine tuning” of critical process parameters within the filed drug application range. However, your firm had determined the original parameters to be insufficient to enable a state of control.

Per your response, your firm has subsequently initiated further CAPA activities to identify the root cause of the (b)(4) capsule dissolution failures. This CAPA will include experimental batches and a technical evaluation of the process to further understand the factors that may contribute to variability in dissolution of your product. After completing this investigation, you commit to revalidating your process.

Your response is inadequate. We note your original validated ranges are not supported, and you did not adequately establish the revised processing parameters to ensure effective remediations for the dissolution failures. In addition, you did not provide sufficient information regarding the design of experimental batch studies to determine root cause of your repeated dissolution failures. We acknowledge you conducted extensive retain testing of product on the market and continue to monitor dissolution stability for product on the market.

In response to this letter, provide the following:

• A copy of your potassium chloride ER capsules investigation (including related studies) into the dissolution failures with actions to thoroughly investigate your process for particle size management and complete retrospective review of all process related changes for potential root cause.
• A copy of your protocol and subsequent report for your DoE study investigating particle size with different (b)(4) content concentrations of (b)(4) solution for your potassium chloride ER capsules. Also, explain whether your DoE studies include other process parameters that could affect (b)(4) efficacy.
• A list of all process changes for the potassium chloride ER capsule product since product launch. Include an evaluation of all changes, including whether each change on their own or a combination of changes could have a potential effect on dissolution.
• A copy of your report from protocol VP/MS/PD/OOS/I111/2024/0040/0024 for assessing the verification batches for (b)(4) capsules.
• A copy of your study protocol and subsequent report from CAPA (CP/I111/2025/0051) to identify the root cause for the (b)(4) capsule dissolution failures using experimental batches.
• A copy of your protocol and subsequent report for completing a technical evaluation of dissolution variability from the (b)(4) capsules manufacturing process.
• A complete review of all drug products with (b)(4) or (b)(4) profiles to determine if additional drug products have adverse process performance or quality signals, including but not limited to, failures related to dissolution or bioavailability.
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality assurance decisions, and is fully supported by executive management.

2. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).

You failed to follow your written stability procedure for your finished drug products. For example, you did not complete timely stability testing for approximately (b)(4) stability samples for U.S. commercial drug products within the stipulated timeline ((b)(4) after sample pull). Stability testing was overdue by 3 months or longer for a large proportion of your samples.

In your response, you provide details for the backlog of pending stability sample testing, root causes for the delays in stability testing, and state all delayed stability sample testing for U.S. commercial products was completed by December 2024, prior to the inspection. You also implemented quality and executive management oversight for reviewing progress of stability testing, metrics, and upcoming stability testing for resource availability. You developed plans to increase quality control (QC) resources to reduce delayed stability sample testing by increasing QC laboratory capacity, purchasing and qualifying additional equipment, and hiring additional personnel. You plan to perform a stability load assessment for stability samples pulled from March 2025 to December 2025 to evaluate the adequacy of resources in your QC laboratory.

Your response is inadequate. You do not include the test results from the delayed stability analyses or a copy of the investigation report with your written response to demonstrate whether backlogged stability testing was completed and adequately investigated for root cause. Also, you do not provide adequate information on your stability load assessment, with pre-defined criteria, to evaluate adequacy of resources for your stability testing program.

Additionally, your impact assessment for the delayed stability analyses does not adequately address the risk to patient safety. Your firm’s failure to perform stability dissolution testing for potassium chloride ER capsules and (b)(4) capsules within the specified testing period led to delays in detecting product quality failures, issuing field alert reports¹ and conducting recalls in a timely manner. For example, in multiple instances, potassium chloride ER capsules dissolution failures were not observed for approximately 100 days after stability samples were pulled.

Without an appropriate ongoing stability program, you lack adequate scientific evidence to support whether your drug products meet established specifications and retain their quality attributes through their labeled expiry.

In response to this letter, provide:

• A copy of the completed stability data from the backlogged stability testing. Include a plan of action for any OOS results found from the stability analyses.
• Your stability load assessment protocol relating to stability samples pulled from March 2025 to December 2025, and the report and CAPA assuring future resource adequacy.
• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability indicating methods.
  o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).
• All procedures that describe these and other elements of your remediated stability program.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your firm failed to perform method validation (or verification, as appropriate) of test methods to ensure they were suitable for their intended use. Your senior leadership confirmed multiple test methods used for incoming API and drug product testing of quality attributes, such as (b)(4) content, identification, and specific rotation, have not been validated, verified, or appropriately transferred.

In your response, you provide a retrospective gap assessment evaluating the adequacy of your method validation/verification studies for API and drug product test methods for the U.S. market. You also acknowledge certain methods had not been validated or verified, and that you have already completed some of the pending studies. The response includes planned completion dates for remaining validation/verification studies (May 31, 2025 for API methods; April 30, 2025 for finished drug products). Additionally, you commit to perform an impact assessment of the drug products distributed to the U.S. market after completion of relevant method validation/verification studies. We acknowledge you completed an interim impact assessment for all drug products in the U.S. market.

Your response is inadequate. Your gap assessment does not adequately address the lack of reference to method validation or verification studies for all appropriate methods, such as your in-house (b)(4) testing and in-house elemental impurities testing for (b)(4) tablets USP (b)(4) mg and (b)(4) mg. Also, your interim impact assessment does not scientifically justify the reliability of your test results in the absence of appropriate method validation/verification studies. System suitability controls and calibration controls for test methods are not an adequate substitute for method validation/verification studies.

Method validation and verification studies are necessary to support reliable determination of identity, strength, quality, purity, and potency of drugs. Without evaluating the validity of methods, you lack the basic assurance that your laboratory data accurately reflects drug product quality.

Refer to FDA’s guidance documents Q2(R2) Validation of Analytical Procedures and Analytical Procedures and Methods Validation for Drugs and Biologics for general principles and approaches for method validation at https://www.fda.gov/media/161201/download and https://www.fda.gov/media/87801/download, respectively.

In response to this letter, provide:

A detailed, independent assessment of all test methods to evaluate if they include sufficiently specific instructions to ensure repeatability, are supported by adequate validation (or verification, for United States Pharmacopeia (USP) compendial methods) studies and are appropriate for their intended use. The assessment should also determine whether test methods used in the stability program are stability-indicating. The scope of the assessment should encompass any tests conducted by your firm or its contract laboratories. Based on this review, provide a detailed protocol to remediate and evaluate the effectiveness of your quality system in ensuring test methods are validated (or verified, where appropriate) and suitable for their intended use.

(b)(4) Production

During the inspection, we observed you manufacturing drug products containing (b)(4), using equipment and air handling units shared with other drug products. Although complete and comprehensive separation of facilities for manufacturing (b)(4) is not required to prevent cross-contamination, it is important to establish and implement robust cross-contamination prevention strategies (e.g., dedicated production suites).² We acknowledge your decision to discontinue the manufacture of (b)(4) drug products for all markets. If you decide to resume manufacturing of your (b)(4) containing drug products, notify FDA and provide your detailed cross-contamination prevention plan for (b)(4).

Repeat Violations at Multiple Sites

FDA cited similar CGMP violations at other facilities in your company’s network.

Glenmark Pharmaceuticals Limited (Himachal Pradesh, India), FEI 3005757050, was issued a warning letter dated October 3, 2019, for violation of, among other items, 21 CFR 211.192 for failing to adequately investigate multiple OOS test results for critical product attributes, such as failed (b)(4) in your (b)(4) cream USP bulk batch. This site was placed on import alert 66-40 on October 25, 2022.

Glenmark Pharmaceuticals Limited (Goa, India), FEI 3004672766, was issued a warning letter dated November 22, 2022, for violation of, among other items, 21 CFR 211.192 for inadequate investigation of OOS results from content uniformity testing of your desmopressin acetate tablets.

Glenmark Pharmaceuticals Inc., (North Carolina, U.S.A.), FEI 3011585599, was issued a warning letter dated June 20, 2023, for various CGMP violations of the FD&C Act.

These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

Drug Production Ceased and Suspended

We acknowledge your commitment to cease production of potassium chloride ER capsules and suspend production of (b)(4) capsules at this facility for the U.S. market. In response to this letter, clarify whether you intend to resume manufacturing potassium chloride ER capsules and/or (b)(4) capsules for the U.S. market at this facility in the future.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPAs.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Glenmark Pharmaceuticals Limited, located at Phase – II, Sector III, Plot No 2, Pharma Zone, SEZ, Pithampur, Madhya Pradesh, 454774 India, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days.³ Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3008565058 and ATTN: Sai Dharmaraj.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

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1 Refer to FDA’s guidance document Field Alert Report Submission for guidance on reporting relevant information for a FAR https://www.fda.gov/media/114549/download.

2 Refer to Appendix B (https://www.fda.gov/media/159358/download) 

3 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.